This proposal describes several novel synthetic strategies to natural products focused on the synthesis and application of beta-lactones (2-oxetanones). New syntheses and transformations of underutilized beta-lactones are proposed for the concise preparation of Omuralide and salinosporamide derivatives, potential species-specific proteasome inhibitors, and the haterumalides, novel marine, macrolide cytotoxic agents. We propose development of an intramolecular, nucleophile-catalyzed, aldol-lactonization (NCAL) process, which uniquely merges catalytic, asymmetric heterocycle synthesis with beta-lactone synthesis. Applications to a highly concise, versatile strategy to Omuralide and salinosporamide derivatives, which are extremely useful tools in biology for study of proteasome function, are proposed. Development of a novel, tandem Mukaiyama aldol-lactonization-cyclization-addition sequence, proceeding through a silylated beta-lactone intermediate, for the synthesis of terahydrofurans and tetrahydropyrans will be applied to a convergent total synthesis of the haterumalides, new marine, antitumor macrolides. This research will expand access to optically active beta-lactones and expand their utility as synthetic intermediates, make available highly concise strategies to Omuralide and salinosporamide derivatives as potential anti-parasitic agents and as generally useful tools for study of proteasome function, verify the structure of the haterumalides and provide access to derivatives useful for mechanism of action studies.